期刊
ORGANIC PROCESS RESEARCH & DEVELOPMENT
卷 20, 期 9, 页码 1566-1575出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.oprd.6b00094
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资金
- Wallonia Region DGO 6 (direction generale operationnelle de l'Economie, de l'Emploi et de la Recherche)
An asymmetric synthesis of the novel antiepileptic drug Brivaracetam 1 is described. The stereochemistry of the 4-n-propyl substituent is introduced by a biocatalytic resolution of (rac)-methyl 2-propylsuccinate 4-tert-butyl ester 4. The selection of the resolution substrate and the screening of enzymes were carried out from our in-house screening platform. The development and scale-up of the best conditions, including solvent media, pH control, workup, and enzyme supply, led up to a successful demonstration conducted at 1 kg scale in a 10 L vessel. The chiral intermediate (R)-2-propylsuccinic acid 4-tert-butyl ester 6 was reproducibly obtained in 42% yield and 97% ee all along the development. The control of the stereochemistry via the biocatalytic resolution allowed the production of Brivaracetam 1 within the required commercial quality specifications.
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